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Santhosh Sethuramanujam, Malcolm Slaughter; Regulated NMDA signaling in transient and sustained pathways. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3405.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate and compare the role of presynaptic inhibitory circuits in activation of synaptic NMDA receptors (NMDARs) in sustained ON (ONs), sustained OFF (OFFs) and transient ON-OFF (ONt-OFFt) retinal ganglion cells (RGCs).
Spike activity and light evoked EPSCs (L-EPSCs) induced by a red, small spot stimulus (660nm, 200µm diameter, 1s) were monitored in RGCs in the whole mount larval tiger salamander retina. The glutamate output of bipolar cells was measured by the total charge in the EPSC.
The NMDA component of L-EPSCs was measured by the current blocked by D-AP5. The NMDA component of the L-EPSC was small under control conditions in all RGCs (ONs=12%, OFFs=-7%, ONt=8%, OFFt=17%). Picrotoxin & strychnine (PTX+STR) increased all L-EPSCs (ONs=2X, OFFs=1.4X, ONt 9X, OFFt=5X) and increased the percentage of the NMDA component (ONs=32%, OFFs= 39%, ONt=75%, OFFt=61%). TBOA promotes glutamate spillover and also increased the NMDA component, except in the OFFs cell (ONs=54%, OFFs=-11%, ONt=51%, OFFt=50%). Hence, PTX+STR disinhibit NMDAR activation. The OFFs RGC NMDARs are not perisynaptic based on TBOA results; hence PTX+STR disinhibit silent synapses. STR increased the NMDA component of ONt cells (ONt=51%) while GABAA block did not (ONt=5%). They both enhanced the OFFt NMDA component (28% vs 23%). In ONt-OFFt cells, increasing the duration of the stimulus selectively increased the OFFt L-EPSC. In half the cells, the OFFt NMDA component was smaller in a 1s stimulus (19%) than a 2s stimulus (36%). However, if the ON pathway was blocked (L-AP4) then OFFt NMDA components were similar (44% vs 42%), indicating a crossover inhibition of the ON to the NMDAR OFF pathway.
L-EPSCs in RGCs consist of AMPA/KA and NMDA components. The NMDA component is small because of presynaptic inhibition. When this inhibition is blocked, NMDARs produce the majority of the light evoked synaptic current in transiently responding RGCs. The rank order of this inhibition is ONt>OFFt>OFFs=ONs. Glycine inhibition accounts for most feedback in the ONt pathway. In the OFFs RGC pathway, where glutamate spillover can be discounted, presynaptic inhibition silences synaptic sites. One example of feedback silencing of NMDAR circuits is the ONt cross inhibition of the OFFt pathway, where a large NMDA component is revealed when the ON pathway is blocked.
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